This Application is a 371 PCT/DK98/00183 filed May 7, 1998 which claims benefit of Provisional application Ser. No. 60/046,011, filed May 9, 1997.
Sertindole is a well known antipsychotic drug having the formula 
The compound was disclosed in U.S. Pat. No. 4,710,500 and the antipsychotic activity thereof was described in U.S. Pat. No. 5,112,838. Sertindole is a potent centrally acting 5-HT2 receptor antagonist in vivo and has further been disclosed to be active in models indicative of effects in the treatment of anxiety, hypertension, drug abuse and cognitive disorders. Recently, it has been reported to show antipsychotic effect in clinical studies, Psychopharmacology (1996) 124:168-175.
U.S. Pat. No. 4,710,500 covered a class of 1-aryl-3-(piperazinyl-, tetrahydropyridyl or piperidyl)indole compounds including sertindole. A number of methods of preparing the compounds were generically disclosed, some of which could be used in the preparation of sertindole. The methods were:
a) reaction of a properly substituted 1-arylindole with a proper 1-substituted 4-piperidone and subsequent reduction of the resulting tetrahydropyridyl compound;
b) arylation of the corresponding 1-unsubstituted indole compound;
c) reduction of the corresponding compound having an oxo group in the 2-position of the indole ring.
Sertindole was specifically exemplified, however, no experimental procedure for its preparation was given.
Perregaard et al., J Med. Chem, 1992, 35, 1092-1101, disclosed a new method of preparing sertindole. This method comprises reaction of the intermediate 5-chloro-1-(4-fluorophenyl)indole with 4-piperidone in a mixture of trifluoroacetic acid and acetic acid, reduction of the resulting 5-chloro-1-(4-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)indole in order to obtain 5-chloro-1-(4-fluorophenyl)-3-(piperidin-4-yl)indole which in turn is reacted with 1-(2-chloroethyl)-2-imidazolidinon in the presence of K2CO3 and KI in methyl isobutyl ketone (MIBK). The 5-chloro-1-(4-fluorophenyl)indole was obtained from the corresponding 3-acetoxy-indole by NaBH4 reduction in methanol and subsequent elimination of H2O under acidic conditions. The 3-acetoxy-indole was prepared from the N-(4fluorophenyl)-N-(2-carboxy-4-chlorophenyl)glycine following literature procedures.
A procedure for preparing the N-(4fluorophenyl)-N-(2-carboxy-4-chlorophenyl)glycine is described in Perregaard et al.,Dansk Kemi, 95, 3. p. 6-9. By this method the glycine is obtained by a copper catalyzed reaction of 2,5-dichlorobenzoic acid with N-(4-fluorophenyl)glycine. The potassium salts of the two acids are used in the presence of K2CO3 in the solvent N-methylpyrrolidone (NMP).
However, it has been found that the above processes are not useful in technical scale. The total yields are too low and the processes involve the use of reactants or solvents that are not suitable and in some cases not allowed in large scale for environmental or safety reasons. Furthermore, due to the aqueous solubility of NMP, the work-up of the reaction is tedious, and regeneration of NMP is costly and time consuming.
Consequently, the present invention relates to a new process useful in technical scale production of sertindole.
It has now been found that the main limiting steps of the process are the preparation of N-(4-fluorophenyl)-N-(2-carboxy-4-chlorophenyl)glycine and the reaction of 5-chloro-1 -(4-fluorophenyl)indole with 4piperidone.
Accordingly, the present invention provides a process for the preparation of N-(4-fluorophenyl)-N-(2-carboxy-4chlorophenyl)glycine comprising reaction of an alkalimetal salt of 2,5-dichlorobenzoic acid with an alkalimetal salt of N-(4-fluorophenyl)glycine in an aqueous, alkaline environment in the presence of a copper catalyst followed by treatment with an aqueous acid, as illustrated in the following reaction scheme: 
wherein M, and M2 are alkali metal ions.
According to Perregaard et al.,Dansk Kemi, 95, a reaction using the potassium salts of the reactants is carried out in NMP. However, the use of NMP necessitated a time consuming extractive work-up, and the reaction afforded substantial amounts of tarry by-products. The reaction temperature was 120-130xc2x0 C.
By carrying out the reaction in aqueous environment instead of NMP, a higher yield and only a negligible amount of tarry by-products are obtained. Furthermore, the work-up procedure is simple and the use of an aqueous medium causes substantial environmental advantages. Finally, the reaction temperature is lowered to the reflux temperature of the aquous medium or below.
In another aspect the invention provides a novel process for preparing 5-chloro-1-(4-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)indole comprising reaction of the 5-chloro-1-(4-fluorophenyl)indole with 4-piperidone in a mixture of a mineral acid and acetic acid, as illustrated in the following reaction scheme: 
By using a mixture of acetic acid and a mineral acid instead of a trifluoroacetic acid-acetic acid mixture, substantial environmental advantages are obtained. Furthermore, trifluoro acetic acid is very volatile and aggressive, accordingly being undesirable for large scale production. Also, the formation of the undesired bis-substituted piperidine may be avoided: 
In yet another aspect, the invention provides a novel process of manufacturing sertindole comprising preparation of N-(4fluorophenyl)-N-(2-carboxy4-chlorophenyl)glycine by a reaction comprising a copper catalysed reaction of an alkalimetal salt of 2,5-dichlorobenzoic acid with an alkali metal salt of N-(4-fluorophenyl)glycine in an aqueous, alkaline environment in the presence of a copper catalyst and/or in which 5-chloro-1-(4-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)indole is obtained by a reaction comprising reaction of the 5-chloro-1-(4-fluorophenyl)indole with 4-piperidone in a mixture of a mineral acid and acetic acid.
The reaction of the alkalimetal salt of 2,5-dichlorobenzoic acid with the alkalimetal salt of N-(4-fluorophenyl)glycine is carried out at an elevated temperature, conveniently at a temperature between 80xc2x0 C. and the reflux temperature of the medium, preferably at about the reflux temperature. Throughout the specification and claims the term aqueous medium is intended to include water and water to which a cosolvent such as ethyleneglycol is added as reaction medium. Preferably water such as demineralised, deionised or destined water is used.
Preferred alkali metal salts of the reactants are the lithium, sodium or potassium salts and conveniently the same salts of the reactants are used. Most preferably the potassium salts are used.
It is important that the HCl formed during the reaction is neutralised in order to avoid undesired side reactions. The reaction medium is made alkaline by addition of a base such as an alkali metal hydroxide, alkali metal acetate, alkali metal carbonate, alkali metal hydrogen carbonate, alkali metal phosphate or alkali metal citrate. Preferably an alkali metal carbonate, such as Li2CO3, Na2CO3 or K2CO3, is used. Conveniently, the same alkali metal as included in the reactants is used. Preferably the base is potassium carbonate. The amount of base is preferably larger than the stoechiometric amount of 2,5-dichlorobenzoic acid. On the other hand, increased [OH] may cause hydrolysis of 2,5-dichlorobenzoic acid, thereby decreasing the yield. Thus, the base may conveniently be added gradually during the process.
The catalyst may be any Cu(0)-catalyst, preferably copper-bronze. It is added in catalytic amounts. The specific amount is not critical and may easily be determined by a person skilled in the art.
The ratio between the amounts of the alkali metal salt of N-(4-fluorophenyl)glycine and the alkali metal salt of 2,5-dichlorobenzoic acid is conveniently from 0.5 to 3.0, preferably 1.0 to 2.5 and most preferably 2.0 to 2.3 mol/mol. Excess N-(4-fluorophenyl)glycine may be regenerated.
The reaction is conveniently carried out in a minimal amount of aqueous solvent still technically feasible. Thus, the yield is improved by decreasing the amount of solvent. The amount of water is preferably less than 10 mL/g 2,5-dichlorobenzoic acid, more preferably less than 5 mL/g in particular less than 3.5 mL/g, most preferably less than 2.5 mL/g.
The reaction time is not very critical and may easily be determined by a person skilled in the art.
The work-up of the product by dilute aqueous acid may be carried out simply by adding the filtered reaction mixture to the dilute acid, thereby precipitating the product. The product may be further purified with hot toluene or by recrystallization from aqueous ethanol. The dilute aqueous acid is preferably hydrochloric acid.
In the reaction of the 5-chloro-1-(4-fluorophenyl)indole with 4-piperidone, the mineral acid used is preferably phosphoric acid, nitric acid, sulfuric acid or hydrochloric acid, such as larger than 30% w/w aqueous HCl, in particular concentrated hydrochloric acid. By concentrated HCl is meant about 37% w/w aqueous HCl.
The 4-piperidone is preferably used as the 4-piperidone-hydrate, hydrochloride.
The reaction should preferably be carried out in excess of piperidone-hydrate hydrochloride. Preferably more than 1.5 equivalents of 4-piperidone pr equivalent 5-chloro-1-(4-fluorophenyl)indole, more preferably more than 1.75, are used. Conveniently, 2.0 equivalents are used.
It is important that sufficient acid is present to allow a sufficient yield. When hydrochloric acid is used as mineral acid, it is preferably used in an amount of at least 2.5 mL concentrated HCl pr. g 5-chloro-1-(4-fluorophenyl)indole. Most preferably the ratio is 3.5 to 5 mL concentrated HCl pr. g 5-chloro-1-(4-fluorophenyl)indole.
The amount of acetic acid has to be sufficient to make the reaction technically feasible. Conveniently, at least 8 mL acetic acid pr. g 5-chloro-1-(4-fluorophenyl)indole is used. Preferably, the amount of acetic acid is more than 10 mL acetic acid pr. g 5-chloro-1-(4-fluorophenyl)indole, most preferably 10-14 mL. The ratio between acetic acid and concentrated HCl is preferably 2:1 to 4:1 vol/vol. The reaction is conveniently carried out by adding, drop-wise, a solution of the 5-chloro-1-(4-fluorophenyl)indole in hot acetic acid to the piperidone-hydrate, hydrochloride or by mixing the two reactants in a mixture of acetic acid and mineral acid followed by reflux. The reaction time is easily determined by a person skilled in the art.
The intermediate may be worked up in a conventional manner. The further process leading to sertindole comprises cyclization of N-(4-fluorophenyl)-N-(2-carboxy-4-chlorophenyl)glycine to the corresponding 3-acetoxy-indole using eg. acetic anhydride in the presence of alkalimetal acetate such as sodium acetate. 5-chloro-1-(4-fluoro)indole is then obtained from the 3-acetoxy-indole by reduction and subsequent elimination of H2O. The resulting 5-chloro-1-(4-fluorophenyl)indole is reacted with 4-piperidone according to the above procedure, the resulting 5-chloro-1-(4-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)indole is reduced in order to obtain 5-chloro-1-(4-fluorophenyl)-3-(piperidin-4-yl)indole which in turn is reacted with 1-(2-chloroethyl)-2-imidazolidinon to obtain sertindole. Alternatively, the 5-chloro-1-(4-fluorophenyl)-3-(1,2,3,6-tetrahydropyridin-4-yl)indole may first be reacted with 1-(2-chloroethyl)-2-imidazolidinon followed by reduction, thereby obtaining sertindole, which may be isolated as an acid addition salt, e.g. the tartrate, or as the free base.
The alkalimetal salt of 2,5-dichlorobenzoic acid and the alkalimetal salt of N-(4-fluorophenyl)glycine used as starting materials are easily prepared from commercially available 2,5-dichlorobenzoic acid and N-(4-fluorophenyl)glycine, respectively, by standard procedures.
Sertindole, as obtained by the process, may conveniently be formulated as described in U.S. Pat. No 5,112,838.